Current treatment of lung cancer includes chemotherapy and radiation as well as EGFR- targeted therapy, the improvement for patient survival has been observed. However, the disease is eventually refractory to these treatments. Thus, there is an unmet need to identify new lung cancer causing gene(s), understand its role in lung carcinogenesis and the chemoradio- and EGFR-TKI-resistance and to develop new targeted therapy. We have detected upregulation and activation of IKBKE, a serine/threonine protein kinase, in a half of non-small cell lung cancers (NSCLC). Ectopic expression of IKBKE transforms lung epithelial AALE-MEK-DD and E10 cells. Knockdown of IKBKE decreases lung cancer stem cell, LCSC, and sensitizes NSCLC cells to chemotherapeutic drug-induced apoptosis, whereas ectopic expression of IKBKE exhibits opposite effects. We have also identified 2 small molecule inhibitors of IKBKE. Mechanistically, we have recently found that IKBKE is activated by activating mutations of KRAS and EGFR (including EGFRT790M) which cause primary and acquired resistance to EGFR-TKI. Furthermore, knockdown of IKBKE selectively reduces cell survival in NSCLC cells in which KRAS and EGFR are dominantly mutated. Based on these findings, we are going to 1) determine the role of gain and loss of function of IKBKE in lung tumorigenesis; 2) ascertain the mechanism and the significance of IKBKE activation by activating mutations of EGFR and KRAS and 3) examine IKBKE regulation of LCSC and IKBKE as a target and its inhibitors as potential agents to overcome EGFR-TKI- and chemo- resistance. PUBLIC HEALTH RELEVANCE: In order to improve lung cancer treatment, novel targeted therapy is urgently needed. Our study points out that IKBKE could play a pivotal role in lung carcinogenesis and that IKBKE is activated by KRAS and EGFR and could serve as a critical target for overcoming EGFR-TKI resistance and for intervening lung cancer. Therefore, further investigation of the role and mechanism of IKBKE in lung oncogenesis and IKBKE inhibitors in EGFR-TKI- and chemo-resistance will not only provide insight into the biology of the IKBKE in lung cancer but will lay a foundation for the development of novel therapeutics.